Mast cells are one of the best-characterized effectors in the allergic response. Mast cell effector functions are now being tied not only to allergic diseases such as asthma, but also to arthritis, multiple sclerosis, and coronary artery disease. Thus, understanding mast call development, function, and survival is clinically significant. Our laboratory has been investigating cytokine-mediated regulation of mast cell biology as a model of immune homeostasis. In this regard, we have found IL-10 to be a multi-functional regulator of mast cell homeostasis. Intedeukin (IL)-10 is a potent regulatory cytokine involved in the Th1 and Th2 immune responses, with close ties to inflammatory diseases such as multiple sclerosis, systemic lupus erythematosus and Crohn's disease. Using IL-10 signaling as a model system, this application will assess the homeostatic effects of Th2 cytokines on mast cell development, function, and survival. Our Specific Aims are: I. To determine the mechanism by which IL-10 induces apoptosis of developing mast cell progenitors II. To determine the mechanism by which IL-10 alters mast cell function II1. III.To determine the mechanism by which co-stimulation with IL-10+IL-4 induces cell cycle arrest and apoptosis of cultured mast cells These aims focus on the role of the transcription factor Stat3 in IL-10 signaling, and will employ primary bone marow-derived mast call populations as an assay system. The goals of this proposal will be accomplished by standard tissue culture and molecular biology approaches, augmented by oligonucleotide microarray analyses of the IL-10-regulated mast call transcriptome and the role of Stat3 in this gene regulation. When completed, these studies will offer a more complete understanding of immune homeostasis and the role Th2 cytokines have in this process. Though most directly related to allergic disease, these studies will impact our understanding of inflammatory diseases such as multiple sclerosis, arthritis, and cardiovascular disease.